Patient and transplant characteristics

Table 1 summarizes transplant characteristics. Between 1999 and 2016, 266 patients received their 1st allo-HSCT for de novo/primary AML (n = 178) or secondary AML (n = 88) after non-TBI-based conditioning with peripheral blood (n = 244) or bone marrow (n = 22) as a stem cell source. The median patient age at allo-HSCT was 55.9 years (IQR, 45.8–61.4). The median follow-up time was 11.4 years (IQR, 9.0–14.9). All patients received reduced-intensity conditioning regimens (RIC-regimens) with Melphalan-based chemotherapy (n = 193) as the most frequent regimen. Table 2 summarizes all conditioning regimens.

Table 1 Patient and transplant characteristics in 266 patientsTable 2 Conditioning regimensAcute and chronic graft-versus-host disease

The 100-day cumulative incidence of grade II-IV aGVHD was 44.4% [95% CI (38.3, 50.2)], while the 2-year and 5-year cumulative incidences of cGVHD (requiring systemic immunosuppression) were 35.0% [95% CI (29.2, 41.4)] and 36.9% [95% CI (31.1, 42.6)]. Table 3 shows graft-versus-host disease characteristics. The most common sites of cGVHD were skin (77.8%), oral mucosa (67.7%) and eyes (59.6%). Most patients had multi-organ involvement of cGVHD (Table 3). The median time of systemic immunosuppressive therapy of cGVHD was 729.0 days (IQR, 337.5–1715.0) in patients developing cGVHD.

Table 3 Chronic graft-versus-host diseaseSecondary solid malignancies including precancerous lesions

Table 4 shows all precancerous lesions, atypical nevi (n = 15) and SSMs (n = 42) with the duration of systemic immunosuppression applied for treatment of cGVHD. In summary, 42 SSMs in 32 patients were recorded. The cumulative incidences of any invasive SSMs at 5, 10 and 15 years were 6.0% [95% CI (3.6, 9.3)], 8.6% [95% CI (5.5, 12.4)] and 12.2% [95% CI (8.1, 17.2)], while the cumulative incidences of death (competing risk) at 5, 10 and 15 years were 54.5% [95% CI (48.3, 60.3)], 56.1% [95% CI (49.9, 61.8)] and 58.0% [95% CI (51.3, 64.1)], respectively.

Table 4 Secondary solid malignancies, precancerous lesions and atypical nevi after allogeneic hematopoietic stem cell transplantationSecondary squamous cell carcinomas

Nineteen invasive SCCs were recorded in 16 patients (Table 4). Fourteen patients developed one SCC, one patient two SCCs and one patient three SCCs. The most common SCCs were cutaneous SCCs (n = 9) and SCCs of the head and neck region (n = 5). The mean time from allo-HSCT to the development of SCCs was 21.3 years [95% CI (20.0, 22.7)]. Figure 1 shows the estimates of the cumulative incidences of secondary SCCs. The cumulative incidences of SCCs at 5, 10 and 15 years were 2.6% [95% CI (1.2, 5.1)], 4.2% [95% CI (2.2, 7.2)] and 8.1% [95% CI (4.6, 12.8)], respectively (Fig. 1). Within this group of SCCs, the cumulative incidences of cutaneous SCCs at 5, 10 and 15 years were 1.1% [95% CI (0.3, 3.1)], 1.1% [95% CI (0.3, 3.1)] and 3.5% [95% CI (1.3, 7.5)].

Fig. 1

Estimates of the cumulative incidences of invasive squamous cell carcinomas (SCCs) with 95% confidence intervals (competing death)

Secondary non-squamous cell carcinomas

In summary, 23 invasive non-SCCs in 16 patients were recorded (Table 4). Ten patients had one non-SCC, five patients had two non-SCCs and one patient had three non-SCCs. The most common cancer types were cutaneous basal cell carcinomas (BCCs, n = 14) and malignant melanomas (n = 3). The mean time from allo-HSCT to the development of invasive non-SCCs was 21.6 years [95% CI (20.3, 23.0)]. The cumulative incidences of non-SCCs at 5, 10 and 15 years were 3.8% [95% CI (1.9, 6.6)], 5.4% [95% CI (3.1, 8.7)] and 6.9% [95% CI (4.0, 10.8)], respectively (Fig. 2). Within this group of non-SCCs, the cumulative incidences of cutaneous BCCs at 5, 10 and 15 years were 1.9% [95% CI (0.7, 4.1)], 2.8% [95% CI (1.2, 5.5)] and 4.3% [95% CI (2.0, 7.9)].

Fig. 2

Estimates of the cumulative incidences of secondary non-squamous cell carcinomas (non-SCCs) with 95% confidence intervals (competing death)

Precancerous lesions and atypical nevi

Eight cutaneous carcinomas in situ, four histologically proven atypical nevi, one actinic keratosis, one intraepithelial neoplasia of the colon, and one vulvar intraepithelial neoplasia (VIN III) in 11 patients were diagnosed (Table 4). The cumulative incidences of precancerous lesions and atypical nevi at 5, 10 and 15 years were 2.6% [95% CI (1.2, 5.1)], 3.8% [95% CI (2.0, 6.7)] and 4.9% [95% CI (2.4, 8.8)], respectively.

Multivariate analysis of secondary solid malignancies and pre-transplantation variables

Table 5 depicts the multivariate analysis of pre-transplantation variables and SSMs using multivariable Fine and Gray proportional hazards regression models. The use of ATG was associated with reduced incidences of SCCs [HR, 0.09, 95% CI (0.02, 0.40); P = 0.002] compared to patients not receiving ATG. The multivariate analysis found no association of ATG with the incidences of non-SCCs (Table 5).

Table 5 Multivariable Fine and Gray proportional hazards regression models of pre-transplantation variables and secondary solid malignanciesCause-specific hazard ratios for development of secondary solid malignancies

Tables 6 and 7 show the cause-specific hazard ratios of aGVHD and cGVHD for SSMs after adjustment of patient age (Model 1) and after adjustment of patient age and ATG (Model 2). Patients with grade II-IV aGVHD had significantly increased rates of SCCs after adjusting with patient age and ATG (Table 6), while patients with cGVHD showed only a trend for increased rates of SCCs (Table 7). GVHD variables did not influence the rates of non-SCCs.

Table 6 Multivariate analysis of acute graft-versus-host disease for secondary solid malignancies: hazard ratios and 95% confidence intervals from cause-specific hazard modelsTable 7 Multivariate analysis of chronic graft-versus-host disease for secondary solid malignancies: hazard ratios and 95% confidence intervals from cause-specific hazard models